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| Author(s): |
Graciana de Azambuja
Total Authors: 1
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| Document type: | Doctoral Thesis |
| Press: | Limeira, SP. |
| Institution: | Universidade Estadual de Campinas (UNICAMP). Faculdade de Ciências Aplicadas |
| Defense date: | 2022-10-07 |
| Examining board members: |
Maria Cláudia Gonçalves de Oliveira;
Dionéia Araldi;
Waldiceu Aparecido Verri Junior;
Adriana Souza Torsoni;
Hosana Gomes Rodrigues
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| Advisor: | Maria Cláudia Gonçalves de Oliveira |
| Abstract | |
Physical exercise is an established strategy to control inflammation related to the development of chronic diseases, such as chronic muscle pain. In this thesis, through two studies, it was hypothesized that: 1) the phenotype of peripheral pro-inflammatory macrophages, as well as the activation of the P2X4 receptor in these cells, contributes to the increase in inflammation and predisposition of skeletal muscle to chronic pain; the activation of PPAR? receptors through physical exercise, alters the modulation of macrophage phenotypes, the profile of cytokines in the tissue and decreases the activation of P2X4 receptors, preventing chronic muscle pain; 2) under physical exercise, skeletal muscle itself has an anti-inflammatory role through the action of the co-activator PGC-1?1 on the NF-?B pathway. These hypotheses were tested using: 1) physical exercise, pharmacological techniques, protein expression analysis and immunohistochemical imaging in a rodent model of inflammation that generates chronic muscular hyperalgesia. 2) in vitro and in vivo transgenic models with high muscle-specific PGC-1? expression, inflammatory stimuli and gene and protein expression analysis in a model of muscle inflammation and degeneration. Results in study 1 demonstrated that: exercise prevented chronic muscle hyperalgesia, through the activation of PPAR? receptors. Activation of PPAR? receptors by 15d-PGJ2 and depletion of muscle macrophages in sedentary animals also prevents chronic hyperalgesia. The acute and chronic period of muscle hyperalgesia were characterized by an increase in inflammatory macrophages and activation of P2X4, where exercise had a preventive role, as well as increased the phenotype of anti-inflammatory macrophages. Also exercise through PPAR? activation induces a decrease in the P2X4 pathway in macrophages, related to the inflammatory process and acute pain. Finally, the concentration of IL-1? in the muscle is elevated in the acute phase, which was also prevented by exercise through the activation of PPAR? receptors. Exercise increased the concentration of IL-10 in the acute and chronic phases, but only in the chronic phase through PPAR? receptors. Results in study 2 demonstrated that: the muscle cell with high expression of PGC-1?1 has high expression of I?B? and, under inflammation, there is a low expression of IKK? and p65. In both in vitro and in vivo inflammatory models, increased expression of inflammatory genes related to the transcription factor NF-?B, is prevented when PGC-1?1 is overexpressed. Our findings suggest that physical exercise activates PPAR? receptors and increases anti-inflammatory responses in muscle tissue through the modulation of macrophage phenotype and pathway, and cytokine profile, thus preventing the establishment of chronic muscle pain, demonstrating the importance of macrophage cell modulation. Furthermore, it is suggested that the action of physical exercise on muscle involves the activation of the co-activator PGC-1?1, exerting a great anti-inflammatory role, local and systemic. These results further highlight the potential of physical exercise, and new molecular mechanisms to modulate inflammatory conditions and the related chronic muscle pain (AU) | |
| FAPESP's process: | 18/13599-1 - Inflammatory mechanisms underlying muscle pain chronification and its prevention by physical exercise: study of macrophages, PPAR gamma and P2X4 receptors involvment |
| Grantee: | Graciana de Azambuja |
| Support Opportunities: | Scholarships in Brazil - Doctorate |